Radiotherapy and Oncology

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1 Radiotherapy and Oncology 9 (29) Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: Postmastectomy irradiation High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: A subgroup analysis of DBCG 82 b&c q Marianne Kyndi a,b, *, Marie Overgaard c, Hanne M. Nielsen a, Flemming B. Sørensen b, Helle Knudsen d, Jens Overgaard a a Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark b Department of Pathology, Aarhus University Hospital, Denmark c Department of Oncology, Århus University Hospital, Denmark d Department of Pathology, Herlev Hospital, Denmark article info abstract Article history: Received 26 April 28 Received in revised form 28 April 28 Accepted 28 April 28 Available online 28 May 28 Keywords: Breast cancer Local recurrence Postmastectomy radiotherapy Randomized study Tissue microarray Background and purpose: International consensus reports recommend postmastectomy radiotherapy only to patients at high risk of a local recurrence (LR). Materials and methods: The present analysis included 1 out of 383 high-risk breast cancer patients randomly assigned to postmastectomy radiotherapy in the DBCG82 b&c trials. Tissue microarrays had been constructed and sections stained for estrogen, progesterone and HER2 receptors. Median potential follow-up time was 17 years. Endpoints were LR as isolated first event, breast cancer mortality and overall mortality. Results: Among patients randomly assigned to not receive radiotherapy, three prognostic subgroups of LR risk were found. The good defined by at least four out of five favorable criteria (63 positive nodes, tumor size <2 cm, Grade 1 malignancy, estrogen or progesterone receptor positive, HER2 negative), the defined by at least two out of three un-favorable criteria (>3 positive nodes, tumor size >5 cm, Grade 3 malignancy) and finally the the group in between. The smallest absolute reduction in 5-year LR probability (11%) after radiotherapy was seen for the good prognosis group. A similar absolute reduction in 15-year breast cancer mortality after radiotherapy (11%) was seen. The largest absolute reduction in 5-year LR probability after radiotherapy was seen for the poor prognosis group (36%). However, this large LR reduction did not translate into any reduction in 15-year breast cancer mortality (%). Conclusion: Translation of LR reduction into breast cancer mortality reduction after postmastectomy radiotherapy to high-risk breast cancer patients seems to be heterogeneous, with the largest translation occurring within the good prognosis group. Ó 28 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 9 (29) Three theories have been formulated suggesting how distant metastases develop in breast cancer. Dr. William Halsted formulated the first theory, suggesting that breast cancer always begins Abbreviations: CMF, cyclophosphamide methotrexate fluorouracil; CT, computer tomography; DBCG, Danish Breast Cancer Cooperative Group; DM, distant metastases; EBCTCG, Early Breast Cancer Trialists Collaborative Group; ER, estrogen receptor; PgR, progesterone receptor; LR, local recurrence; PM, Postmastectomy radiotherapy; TNM, tumor node metastasis. q The study was conducted on behalf of the DBCG (Danish Breast Cancer Cooperative Group). * Corresponding author. Department of Experimental Clinical Oncology, Aarhus University Hospital, Århus Sygehus, Noerrebrogade 44, Building 5, 2, DK-8 Aarhus C, Denmark. address: kyndi@oncology.dk (M. Kyndi). as a local disease, which over time spread in a contiguous manner through the lymphatics [1]. This theory, though, could not explain that despite surgically well-controlled primary cancer, distant metastases develop in some women, and in reaction to the Halstedian theory, the systemic theory was formulated [2]. The systemic theory suggests that breast cancers either never will metastasize or always have metastasized at the time of diagnosis. This theory, though, fails to explain that some women with node positive disease are cured by locoregional treatment only, and a third hypothesis, the spectrum hypothesis, has been formulated. The spectrum hypothesis synthesizes aspects of the two previous hypotheses suggesting that breast cancer consists of a wide spectrum of diseases, extending from tumors that will never metastasize, to those with the potential to metastasize but without metastases at diag /$34. Ó 28 Elsevier Ireland Ltd. All rights reserved. doi:1.116/j.radonc

2 M. Kyndi et al. / Radiotherapy and Oncology 9 (29) nosis, and to those always presenting with distant micrometastases or larger metastases (unresponsive to the systemic therapy applied) at the time of diagnosis [3]. An overview by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) has been suggested to support a causal link between local control and survival in some patients [4 6]. The EBCTCG overview showed that for every four local recurrences (LR) avoided one breast cancer death over the next 15 years would be avoided [4]. The EBCTCG findings together with findings from mammographic screenings trials, showing that improved local control as well as improved diagnosis results in improved overall survival, have been suggested to refute the systemic hypothesis [5] and implicitly lend support to the spectrum hypothesis. A proportional correlation between 5-year LR risk and 15-year absolute reduction in breast cancer mortality after a locoregional treatment was shown in the EBCTCG overview, as well. Patients having a very little LR risk (less than 1%) had a very small absolute reduction in 15-year breast cancer mortality, whereas patients with a larger LR risk (more than 2%) had a larger absolute reduction in 15-year breast cancer mortality. The overview defined LR risk strictly from outcome but showed as well that LR risk could be described by different clinical pathological parameters, with the largest absolute reduction in 5-year LR probability after postmastectomy radiotherapy (PM) found for patients defined by markers of poor prognosis such as poorly differentiated tumors, large tumor size, estrogen receptor (ER) negative tumors and patients with more than three positive lymph nodes. Defining risk groups from outcome, as was performed in the EBCTCG overview, may be relevant in order to reveal a causal link between LR reduction and a subsequent survival reduction. In a clinical setting, however, it is relevant to define risk groups by prognostic or predictive markers. Although not stated in the overview, it may lend support to what is recommended in consensus reports and widely accepted in many countries, namely that PM should be offered only to patients at a high risk of LR which can be defined by clinical pathological markers [7 15]. In fact, today International consensus reports recommend PM to patients with more than three positive lymph nodes. More than three positive nodes, however, is not only a significant prognostic marker of increased local recurrence probability but is also a very strong prognostic marker of increased probability of distant metastases and reduced survival. This implies, assuming that the spectrum hypothesis explains the natural history of breast cancer most correctly, that positive nodal status not discriminate strictly the tumors benefiting from locoregional treatment (tumors without, but with the potential to develop, distant micrometastases that are unresponsive to the systemic therapy) but is recommended to a group of patients, who have already developed distant unresponsive micrometastases and thus will not be subjected to a survival improvement from a locoregional treatment such as PM. However, if subgroups were defined by combinations of classical clinical pathological markers or from biological markers of poor prognosis the subgroup of patients with more than three positive nodes could perhaps be reduced to patients who had already developed unresponsive distant micrometastases and thereby not subjected to a survival improvement after PM. Moreover, combining markers of good prognosis may reveal subgroups of patients primarily with tumors without distant unresponsive micrometastases, but with the potential to develop such and thereby subjected to a significant survival improvement after PM. In this study, including 1 high-risk breast cancer patients treated with systemic therapy and randomly assigned PM, subgroups, representative of LR probability, will be constructed from combinations of different clinical pathological markers. Subsequently, breast cancer specific and overall survival probability after PM will be recorded for each subgroup of patients. Materials and methods Patients and methods In the period , 383 high-risk Danish Breast Cancer patients were enrolled in the DBCG82 b&c studies. High risk was defined as either positive lymph nodes and/or tumor size larger than 5 cm and/or invasion of tumor to surrounding skin or pectoral fascia. All women had a total mastectomy and a partial axillary dissection. A median of seven lymph nodes was removed from the axilla. The pre-menopausal women were enrolled in the DBCG82 b protocol and were randomized to either radiotherapy + CMF chemotherapy (eight cycles) or CMF chemotherapy alone (nine cycles) [16]. The postmenopausal women were enrolled in the DBCG82 c protocol and were randomized to either radiotherapy + tamoxifen (3 mg daily/1 year) or tamoxifen alone [17]. Long-term clinical follow-up has been performed and is described in detail in a previous publication [18]. A subgroup of 178 patients was selected for an extended biological update. All the patients fulfilled the selection criteria: at least eight lymph nodes surgically removed and available paraffin blocks. Invasive tumor was verified in paraffin embedded tumor blocks from 1 of the patients and cores were transferred to tissue microarrays. Sections from tissue microarrays were immuno-histochemically stained for the ER, progesterone receptor (PgR) and HER2 receptor, for more details see Kyndi et al. [19]. Staging was performed according to the TNM classification, and histological grade was assessed according to the Bloom and Richardson grade [2]. Median potential follow-up time was 17 years. Endpoints to be considered were LR, distant metastases (DM), breast cancer mortality and overall mortality. LR was defined as ipsilateral chest wall failure, ipsilateral axillary or supra/infraclavicular failure. Only isolated LR as first event was considered, that means LR with no subsequent DM within 1 month. Staging procedures at the time of LR included clinical examination, chest X-ray, bone scan and laboratory tests. Liver ultrasonography was performed only in the presence of abnormal liver enzymes or clinical symptoms. DM was defined as any failure outside the ipsilateral mammary region and the regional lymph nodes. In case the patient had contralateral breast cancer and subsequent DM, this was not recorded as DM. Histopathological or cytologic confirmation of DM was not performed routinely and often the diagnosis of DM was based on clinical and radiological findings. Breast cancer specific death was defined as patients who died and were recorded with DM. The v 2 or exact tests were used for testing relationships between variables. Kaplan Meier probability curves were made and tested for differences by a log-rank test. Cox univariate analyses of hazard ratios (HRs) were provided, as well. HRs presented on overall survival and breast cancer specific survival curves were HRs of overall mortality and breast cancer specific mortality. Level of significance was set to 5% and all estimated p-values were twotailed. Statistical calculations were performed using the statistical program STATA version 8.2. In order to match the three prognostic subgroups presented in the EBCTCG overview, patients randomly assigned to not receive PM were separated in three subgroups defined by a combination of prognostic markers of LR risk. Different combinations of poor prognostic markers and of good prognostic markers were examined in Kaplan Meier LR probability plots. The combination of poor prognostic markers defining the subgroup of patients with the highest 5-year LR risk was defined the poor prognostic subgroup and the combination of good prognostic markers defining the subgroup of patients with the smallest 5-year LR risk was defined the good prognostic subgroup. The only additional criteria to be met was a sufficient number of patients in all the three groups of patients (approximately 2 patients). The smallest LR risk at 5 years was found for patients characterized

3 76 Constructed subgroups discriminating response to postmastectomy radiotherapy by at least four out of five favorable criteria: 63 positive lymph nodes; tumor size 62 cm; Grade 1 malignant tumors; hormonal receptor positive tumors; HER2 negative tumors. This good prognostic subgroup consisted of 199 patients and had a 5-year LR probability of 11%. In the other end of the spectrum the subgroup of patients with the highest LR risk was defined by at least two out of three unfavorable criteria: >3 positive lymph nodes; tumor size >5 cm; Grade 3 malignant tumors. This poor subgroup consisted of 28 patients and had a 5-year LR probability of 5%. The remaining 593 patients were defined as the intermediate prognostic subgroup with a 5-year LR probability of 26% (Fig. 1). Results No Radiotherapy 5% 26% 11% p< Fig. 1. Kaplan Meier plot of local recurrence probability among high-risk breast cancer patients randomly assigned to not receive radiotherapy as a function of the good, the intermediate and the poor prognostic subgroups. The subgroup of 1 patients was well distributed between the two randomization arms for all clinical pathological parameters including the three new prognostic subgroups (Table 1). Fig. 2 repeats 5-year LR probability among patients randomized to not receive PM with the LR probability increasing from 11% for the good prognosis group to 5% for the poor prognosis group. Adding PM reduced 5-year LR recurrence probability significantly for all three subgroups. In agreement with the EBCTCG overview the largest absolute reduction in LR probability after PM was seen for the poor prognosis group with a 36% as compared with a 21% for the intermediate prognosis group and an 11% absolute reduction for the good prognosis group. For the good prognosis group, an 11% absolute reduction in 15-year breast cancer mortality after PM was seen. Roughly, this was a one to one translation of the LR reduction into breast cancer mortality reduction after PM. A higher mortality was found for the intermediate prognosis group as compared with the good prognosis group. In addition, an 11% absolute reduction in 15-year breast cancer mortality after PM was seen, accounting approximately half the absolute reduction in LR probability after PM. Finally, the highest mortality was seen for the poor prognosis group, reaching 81%. Notably, the very large absolute reduction in LR probability after PM was not translated into an absolute reduction in 15-year breast cancer mortality. Fig. 3 provides Kaplan Meier plots of local recurrence probability, breast cancer specific survival and overall survival as a function of PM. A continuously improved breast cancer specific and overall survival Table 1 Distribution of different clinical pathological parameters including the three constructed subgroups, among 1 high-risk breast cancer patients randomly assigned to receive or not receive postmastectomy radiotherapy No v 2 All 489 (49%) 511 (51%) Protocol Pre (82b) 267 (54%) 296 (58%).3 Post (82c) 222 (46%) 215 (42%) Tumor size (mm) < (35%) 19 (37%) (53%) 242 (47%) >5 59 (12%) 79 (15%) Positive nodes None 29 (6%) 31 (6%) (46%) 22 (43%) >3 238 (49%) 26 (51%) TNM Stage (4%) 189 (37%) (6%) 322 (63%) Histopathology Ductal 428 (88%) 427 (84%).1 Non-ductal 61 (12%) 84 (16%) Malignancy grade (ductal only) Grade 1 98 (23%) 97 (23%).7 Grade (5%) 223 (52%) Grade (27%) 17 (25%) ER Positive 327 (67%) 344 (67%).4 Negative 16 (33%) 167 (33%) Unknown 2 (%) (%) PgR Positive 283 (58%) 313 (61%).3 Negative 25 (42%) 198 (39%) Unknown 1 (%) (%) HER2 Negative 376 (77%) 44 (79%).6 Positive 11 (22%) 16 (21%) Unknown 3 (1%) 1 (%) Constructed subgroups 98 (2%) 11 (2%) (59%) 33 (59%) 11 (21%) 17 (21%) Local rec. (5-year) + Breast cancer mortality + (15-year) 33% 22% 26% 61% 5% 5% 81%81% 11% 14% 5% % Fig. 2. Histogram of 5-year local recurrence probability and 15-year breast cancer mortality within the good, the intermediate and the poor prognostic subgroups in high-risk breast cancer patients randomly assigned to receive or not receive postmastectomy radiotherapy (). after PM was seen throughout the total period of 15 years for the good and the intermediate prognostic subgroups. For the

4 M. Kyndi et al. / Radiotherapy and Oncology 9 (29) % LR All HR.11 (.3-.49) p=.4 % LR All HR.15 (.8-.28) 26% p<.1 5% % 14% LR All HR.22 (.1-.48) p< Disease specific survival (%) p= HR.59 ( ) 78% 67% Disease specific survival (%) p=.6 5% 39% HR.74 ( ) Disease specific survival (%) p= HR 1.16 ( ) 19% 19% Overall survival (%) p= HR.75 ( ) 65% 53% Overall survival (%) p=.3 39% 3% HR.81 ( ) Overall survival (%) p= % % HR 1.4 ( ) Fig. 3. Kaplan Meier probability plots of local recurrence, breast cancer specific survival and overall survival within the good, the intermediate, and the poor subgroups of patients as a function of postmastectomy radiotherapy (). Hazard ratios (HR)s of local recurrences and mortality after postmastectomy radiotherapy and p-values are presented as well. poor prognosis subgroup, however, neither breast cancer specific nor overall survival was significantly improved after PM throughout the 15-year period. Discussion In addition to the results from mammographic screening trials and the most recent EBCTCG overview this study supports the spectrum hypothesis. Within, this subgroup analysis of 1 high-risk postmastectomy breast cancer patients, the largest translation from LR reduction into breast cancer mortality reduction after PM was found for the good prognosis group, defined by several good prognostic markers. This finding is consistent with the majority of these high-risk tumors having the potential to metastasize, but not yet metastasized at diagnosis. In the intermediate prognosis group a smaller translation from LR reduction into breast cancer mortality reduction was found, indicating that a larger fraction of the tumors may have already had developed distant micrometastases, which were unresponsive to the systemic therapy given. Finally, for the poor prognosis group, defined by at least two out of three poor prognostic markers, practically no translation was found from LR reduction into breast cancer mortality reduction after PM, indicating that most of the tumors may have

5 78 Constructed subgroups discriminating response to postmastectomy radiotherapy developed distant unresponsive micrometastases at time of diagnosis. Several explanations can be listed explaining why our results are in disagreement with international consensus guidelines and differ from what is common perception. The notion that node positive patients at low LR risk should experience no overall survival advantage after PM is primarily based on two observations. First, that early studies examining postmastectomy radiotherapy found an excess cardiac death and no overall survival improvement after PM [21 23], and second, that the first worldwide overview of all the trials of postoperative radiotherapy showed only a small, but not statistically significant, survival improvement after radiotherapy [24]. The overview, however, included many trials counting limited number of patients and trials in which patients were treated with outdated treatment volumes and techniques. Besides, the trials were not subdivided according to whether systemic therapy was provided. In fact, significant overall survival improvements were reported in an overview of randomized trials of PM in which systemic therapy was given [25] and was found in the most recent EBCTCG worldwide overview, as well [4]. In addition, significant survival improvements have been reported for subgroup analyses of patients with 1 3 positive lymph nodes [26 28], and was weakly indicated in the most recent EBCTCG overview, as well (web Fig. 2d) [4]. Moreover, in the DBCG82 trials large effort was made avoiding radiation induced cardiac deaths, resulting in no evidence of such [29]. Against the findings could be argued that improved systemic therapy regimens, now including anthracyclines, taxanes and trastuzumab, may lead to more cardiotoxic events. Furthermore that the improvement in the systemic therapy regimens may result in fewer LR and that the observed survival improvement among patients with 1 3 positive nodes and for our good prognosis subgroup may not be evident in a recent study. The cardiotoxic events, however, may be counterbalanced by improvements in radiation therapy techniques, in particular with the use of computerized tomography (CT), resulting in avoidance of high-dose radiation therapy to the heart. Altogether, these issues may be clarified in the prospective randomized international SU- PREMO trial including patients with 1 3 positive lymph nodes (ISRCTN ). The finding of practically no absolute reduction in breast cancer mortality after locoregional PM for patients with the highest LR risk, when defined by a combination of poor prognostic criteria, is also controversial. In comparison, significant overall mortality reductions after PM have been reported for patients with more than three positive lymph nodes in the DBCG82 b&c studies and the British Columbia Randomized Radiation trial [27,28], was indicated in the most recent EBCTCG overview [4] (web Fig. 2e), and was found in this subgroup of 1 patients, as well. It illustrates the large complexity within this area. The poor prognosis subgroup defined by at least two out of three poor prognostic criteria counts less than half the patients with more than three positive nodes in this series of 1 patients. It could be argued that this poor prognosis subgroup identify patients with more than three positive nodes and the biologically most aggressive disease, with occult unresponsive micrometastases, whereas patients with more than three positive nodes, as the only poor prognostic criteria, may have less aggressive disease without occult unresponsive micrometastases. Our results differ from the most recent EBCTCG overview, as well, in which the largest mortality reduction was reported for patients at highest LR risk. This disagreement may, however, be ascribed the construction of subgroups, which is also illustrated by the 15-year breast cancer mortality level differing notably between the overview and the DBCG82 b&c study. In the overview, in which subgroups were constructed from outcome, only a slight increase in 15-year breast cancer mortality level was seen among patients receiving no therapy, from 42.3% in the low-risk group to 53.4% in the high-risk group. In the DBCG82 b&c study, in which subgroups were constructed from prognostic markers, 15-year breast cancer mortality increased from 33% in the low-risk group to 81% in the high-risk group randomized to receive no PM. This clearly indicates that the high-risk group defined in the DBCG82 study had more aggressive tumors as compared with the high-risk group in the recent EBCTCG overview, despite both high-risk groups were defined from LR risk. Another or an additional explanation could be that the LR risk subgroups in the EBCTCG overview were defined from outcome in a very large and heterogeneous group of patients receiving many different treatments. Fourteen subgroups were made according to local treatment differences (radiotherapy vs. no radiotherapy, surgery vs. less surgery, surgery vs. less surgery and radiotherapy). These subgroups were subdivided by nodal status making a total of 24 treatment comparisons. These treatment comparisons were then grouped arbitrarily into the three LR risk categories according to the absolute reduction in the 5-year LR risk. However, the authors informed that most of the substantial absolute reduction in LR risk involved the addition of radiotherapy, which resulted in an unbalanced distribution of treatments to the three LR risk categories with allocation of only one study of PM (node negative patients) to the <1% LR risk subgroup and five comparisons of PM (node positive) (including the DBCG82 b&c studies) to the 1 2% and the >2% LR risk subgroups (web Fig. 5). A consequence may be that the results from the overview cannot be directly transferred to high-risk (primarily node positive) breast cancer patients treated with PM. It could be argued that not all 1 patients may have benefited from the systemic therapy given, and that distant responsive micrometastases may not have been eradicated for those patients. This argument may relate to the hormonal receptor negative postmenopausal patients who had probably no effect of treatment with tamoxifen. This may have resulted in no survival improvement after PM due to the non-eradicated distant micrometastases. It can be questioned that these patients were analyzed together with the remaining patients, probably subjected to some benefit from the systemic therapy provided. However, excluding these patients from the analyses did not change the final results of the study. Another argument could be that recent improvements in the systemic therapy may question the relevance of our findings. We have previously shown that PM does not result in a notably survival reduction among patients with hormonal receptor negative and HER2 positive tumors [3]. The addition of Herceptin and perhaps also anthracyclines may reduce the occurrence of distant unresponsive micrometastases notably, and may thereby reduce the number of patients not benefiting from PM. Another point of criticism is our use of Kaplan Meier plots for separating the three subgroups prognostic of LR. This statistical methodology is not appropriate for endpoints subjected to competing risk, such as LR. Kaplan Meier plots may underestimate the true rates of LR by assuming that patients with competing risk (DM, contra lateral breast cancer, death) have a LR risk equivalent to that of the overall population in the study, although these patients probably have more aggressive disease and thereby a higher LR risk. In this study, the underestimation of LR may be of largest magnitude for the poor prognosis group having most competing DM and deaths. We chose to use the Kaplan Meier methodology nevertheless, because this study primarily was considered as a proof of principle study, and the exact magnitude of the LR probabilities was of minor importance. Of larger importance was that the same pattern was seen when the subgroups were constructed differently, with a high absolute reduction in breast cancer mortality among patients at low risk of LR and a small or no absolute reduction in breast cancer mortality among patients at high risk of LR. In conclusion, this study highly supports the spectrum hypothesis formulated by Samuel Hellman and illustrates the large com-

6 M. Kyndi et al. / Radiotherapy and Oncology 9 (29) plexity associated with defining postmastectomy treatment indications. In particular, is the complexity associated with defining LR risk from prognostic markers illustrated, and the importance of considering different subtypes implicated in the spectrum hypothesis when recommending postmastectomy radiotherapy. Acknowledgements This study was supported by grants from the Danish Cancer Society and the University of Aarhus, the Danish Medical Research council, The Novo Nordisk Reseach foundation, and ML Jørgensen and Gunnar Hansen s foundation. The funding sources had no role in the writing of the manuscript. The authors thank Stine Walther Nielsen, Tine Bovtrup, Birthe Hermansen and Mogens M. Johannesen for excellent technical assistance. References [1] Halsted WS. The results of radical operations for the cure of carcinoma of the breast. Ann Surg 197;46:1. [2] Fisher B. 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